Abstract
The ATPase RIG-I senses viral RNAs that contain 5'-triphosphates in the cytoplasm. It initiates a signaling cascade that activates innate immune response by interferon and cytokine production, providing essential antiviral protection for the host. The mode of RNA 5'-triphosphate sensing by RIG-I remains elusive. We show that the C-terminal regulatory domain RD of RIG-I binds viral RNA in a 5'-triphosphate-dependent manner and activates the RIG-I ATPase by RNA-dependent dimerization. The crystal structure of RD reveals a zinc-binding domain that is structurally related to GDP/GTP exchange factors of Rab-like GTPases. The zinc coordination site is essential for RIG-I signaling and is also conserved in MDA5 and LGP2, suggesting related RD domains in all three enzymes. Structure-guided mutagenesis identifies a positively charged groove as likely 5'-triphosphate-binding site of RIG-I. This groove is distinct in MDA5 and LGP2, raising the possibility that RD confers ligand specificity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphatases / chemistry
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Adenosine Triphosphatases / genetics
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Adenosine Triphosphatases / immunology
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Adenosine Triphosphatases / metabolism*
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Animals
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Binding Sites / genetics
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Cell Line
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DEAD Box Protein 58
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DEAD-box RNA Helicases / chemistry
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / immunology
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DEAD-box RNA Helicases / metabolism*
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Dimerization
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Humans
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Immunity, Innate / physiology
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Interferon-Induced Helicase, IFIH1
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Interferons / genetics
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Interferons / immunology
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Interferons / metabolism
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Polyphosphates / chemistry
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Polyphosphates / immunology
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Polyphosphates / metabolism*
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Protein Structure, Tertiary / genetics
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RNA Caps / chemistry
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RNA Caps / genetics
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RNA Caps / immunology
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RNA Caps / metabolism*
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RNA Helicases / chemistry
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RNA Helicases / genetics
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RNA Helicases / immunology
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RNA Helicases / metabolism
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RNA, Viral / chemistry
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RNA, Viral / genetics
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RNA, Viral / immunology
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RNA, Viral / metabolism*
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Receptors, Immunologic
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Structural Homology, Protein
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Structure-Activity Relationship
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Substrate Specificity / genetics
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Zinc / chemistry
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Zinc / immunology
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Zinc / metabolism
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rab GTP-Binding Proteins / chemistry
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rab GTP-Binding Proteins / genetics
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rab GTP-Binding Proteins / immunology
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rab GTP-Binding Proteins / metabolism
Substances
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Polyphosphates
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RNA Caps
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RNA, Viral
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Receptors, Immunologic
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Interferons
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DHX58 protein, human
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Adenosine Triphosphatases
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RIGI protein, human
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IFIH1 protein, human
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DEAD Box Protein 58
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DEAD-box RNA Helicases
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Interferon-Induced Helicase, IFIH1
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RNA Helicases
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rab GTP-Binding Proteins
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Zinc
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triphosphoric acid